Process for preparing spiro[2.5]octane-5,7-dione

ABSTRACT

Disclosed is a method for the synthesis of spiro[2.5]octane-5,7-dione useful as intermediate in the manufacture of pharmaceutically active ingredients. Also disclosed are novel intermediates used in the synthesis of this compound.

TECHNICAL FIELD

This invention relates to a novel process or method for the synthesis ofspiro[2.5]octane-5,7-dione useful as intermediate in the manufacture ofpharmaceutically active ingredients.

BACKGROUND

Spiro[2.5]octane-5,7-dione is an important intermediate for theproduction of pharmaceutically active ingredients. The synthesis of thisintermediate has been described in WO 2006/72362 and is quite complex,costly and unattractive for larger quantities. Therefore there is a needfor a new synthesis route to manufacture spiro[2.5]octane-5,7-dioneefficiently and in the high quality needed for pharmaceuticalintermediates.

DESCRIPTION OF THE INVENTION

The present invention provides an efficient process for the manufactureof spiro[2.5]octane-5,7-dione having the formula

in the steps as described herein below.

A general process for preparing spiro[2.5]octane-5,7-dione is outlinedin Scheme 1. In one embodiment, the present invention is directed to thegeneral multi-step synthetic method for preparingspiro[2.5]octane-5,7-dione as set forth in Scheme 1 below. In otherembodiments, the invention is directed to each of the individual stepsof Scheme 1 and any combination of two or more successive steps ofScheme 1. The invention may also be directed to the intermediatecompounds, e.g. as set forth in Scheme 1.

An alternative general process for preparing spiro[2.5]octane-5,7-dioneis outlined in Scheme 2. In one embodiment, the present invention isdirected to the general multi-step synthetic method for preparingspiro[2.5]octane-5,7-dione as set forth in Scheme 2 below. In otherembodiments, the invention is directed to each of the individual stepsof Scheme 2 and any combination of two or more successive steps ofScheme 2. The invention may also be directed to the intermediatecompounds, e.g. as set forth in Scheme 2.

Thus, in one aspect, the present invention relates to a process for themanufacture of spiro[2.5]octane-5,7-dione having the formula

said process comprising the following steps (Scheme 1):

Accordingly, the present invention further relates to one or more of theabove steps of Scheme 1.

With reference to the steps shown in Scheme 1 of the invention, aprocess or method according to the present invention comprises one ormore of the following:

-   -   hydrolizing (1-cyanomethyl-cyclopropyl)-acetonitrile to form        (1-carboxymethyl-cyclopropyl)-acetic acid (such as e.g. in the        presence of a suitable base, such as aqueous potassium        hydroxide),    -   cyclizing (1-carboxymethyl-cyclopropyl)-acetic acid to form        6-oxa-spiro[2.5]octane-5,7-dione (such as e.g. in the presence        of a suitable carboxylic acid anhydride forming agent, such as        acetanhydride, preferably in mesitylene as reaction solvent, at        elevated temperature),    -   reacting 6-oxa-spiro[2.5]octane-5,7-dione with an alcohol (e.g.        C₁-C₆ alkanol, preferably C₁-C₄ alkanol, more preferably C₁-C₃        alkanol or even more preferably C₁-C₂ alkanol, particularly        methanol) to form (1-alkoxycarbonylmethyl-cyclopropyl)-acetic        acid (such as e.g. in the presence of 4-dimethylaminopyridine as        promotor, preferably in a reaction medium comprising an excess        of the alcohol and/or toluene, at elevated temperature),    -   converting (1-alkoxycarbonylmethyl-cyclopropyl)-acetic acid into        the corresponding (1-alkoxycarbonylmethyl-cyclopropyl)-acetic        acid chloride (such as e.g. in the presence of a suitable        carboxylic acid chloride forming agent, such as thionyl        chloride, preferably in the presence of N,N-dimethylformamide as        promotor, preferably in toluene as reaction medium),    -   methylation of (1-alkoxycarbonylmethyl-cyclopropyl)-acetic acid        chloride to form [1-(2-oxo-propyl)-cyclopropyl]-acetic acid        alkyl ester (such as e.g. in the presence of a suitable        nucleophilic methylating agent, such as e.g. a methyl magnesium        (Grignard) in the presence of an iron containing catalyst, or a        methyl copper reagent, preferably in a reaction solvent        comprising toluene and/or tetrahydrofurane),    -   cyclizing [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester        to form spiro[2.5]octane-5,7-dione (such as e.g. in the presence        of a suitable base, such as a respective metal alcoholate (e.g.        sodium methanolate, sodium ethanolate, or the like), preferably        in a reaction solvent comprising tetrahydrofurane and/or the        respective alcohol).

Further thus, in another aspect, the present invention relates to aprocess for the manufacture of spiro[2.5]octane-5,7-dione having theformula

said process comprising the following steps (Scheme 2), either viavariant I or via variant II:

Accordingly, the present invention further relates to one or more of theabove steps of Scheme 2.

With reference to the steps shown in variant I of Scheme 2 of theinvention, a process or method according to the present inventioncomprises one or more of the following:

-   -   ring opening methylation of 6-oxa-spiro[2.5]octane-5,7-dione to        form [1-(2-oxo-propyl)-cyclopropyl]-acetic acid (such as e.g. in        the presence of a suitable nucleophilic methylating agent, such        as e.g. a methyl copper reagent, or a methyl magnesium        (Grignard) reagent in the presence of a metal (e.g. Fe or Cu)        containing catalyst, preferably in a reaction solvent comprising        tetrahydrofurane),    -   esterification of [1-(2-oxo-propyl)-cyclopropyl]-acetic acid        with an alcohol (e.g. C₁-C₆ alkanol, preferably C₁-C₄ alkanol,        more preferably C₁-C₃ alkanol or even more preferably C₁-C₂        alkanol, particularly methanol) to form        [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester (such as        e.g. in the presence of a suitable acid (e.g. hydrochloric        acid), preferably in a suitable reaction solvent comprising an        excess of the alcohol and/or mesitylene, at elevated        temperature),    -   cyclizing [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester        to form spiro[2.5]octane-5,7-dione (such as e.g. in the presence        of a suitable base, such as a respective metal alcoholate (e.g.        sodium methanolate, sodium ethanolate, or the like), preferably        in a reaction solvent comprising tetrahydrofurane and/or the        respective alcohol).

With reference to the steps shown in variant II of Scheme 2 of theinvention, a process or method according to the present inventioncomprises one or more of the following:

-   -   reacting 6-oxa-spiro[2.5]octane-5,7-dione with        N,O-dimethylhydroxylamine to form        {1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid        (such as e.g. in the presence of a suitable base (e.g.        pyridine)),    -   methylation of        {1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid        to form [1-(2-oxo-propyl)-cyclopropyl]-acetic acid (such as e.g.        in the presence of a suitable nucleophilic methylating agent,        such as methyl lithium, methyl copper or methyl magnesium        (Grignard) reagent, optionally in the presence of a metal (e.g.        Fe or Cu) containing catalyst, preferably in a reaction solvent        comprising tetrahydrofurane),    -   esterification of [1-(2-oxo-propyl)-cyclopropyl]-acetic acid        with an alcohol (e.g. C₁-C₆ alkanol, preferably C₁-C₄ alkanol,        more preferably C₁-C₃ alkanol or even more preferably C₁-C₂        alkanol, particularly methanol) to form        [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester (such as        e.g. according to above-described conditions),    -   cyclizing [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester        to form spiro[2.5]octane-5,7-dione (such as e.g. according to        above-described conditions).

In certain more detailed embodiments of the invention, the presentinvention relates to the process and/or the individual process stepssubstantially as described by way of example in the following examples.

Further, the invention relates to a compound useful as intermediateselected from:

(1-Carboxymethyl-cyclopropyl)-acetic acid,

6-Oxa-spiro[2.5]octane-5,7-dione,

(1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid,

(1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester,

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester,

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid, and

{1- [(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid,

or a tautomer or salt thereof.

In a further embodiment, the present invention is not limited to the useof a methyl ester of formula

within the processes or methods according to the present invention, inaddition to the respective methyl esters, a broader genus of esters offormula

in each of which R may be C₁-C₆ alkyl, preferably C₁-C₄ alkyl (such ase.g. methyl, ethyl, propyl, isopropyl, or the like), more preferablyC₁-C₃ alkyl or even more preferably C₁-C₂ alkyl, particularly methyl,may be considered.

Accordingly, in alternative embodiments, the present invention refers toprocesses or methods as disclosed hereinabove or hereinbelow (e.g.Scheme 1 or Scheme 2) wherein a compound of formula

in each of which R is C₁-C₆ alkyl, preferably C₁-C₄ alkyl (such as e.g.methyl, ethyl, propyl, isopropyl, or the like), more preferably C₁-C₃alkyl or even more preferably C₁-C₂ alkyl, particularly methyl, is usedor involved instead of a compound of formula

respectively.

In a particular embodiment, the present invention provides and relatesto the following compound or a salt thereof as well as its preparation:

6-Oxa-spiro[2.5]octane-5,7-dione having the formula:

In a particular embodiment, the present invention provides and relatesto the following compound or a salt thereof, as well as its preparation:

(1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid having the formula:

In a particular embodiment, the present invention provides and relatesto the following compound or a salt thereof, as well as its preparation:

(1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester having theformula:

In a particular embodiment, the present invention provides and relatesto the following compound or a salt thereof, as well as its preparation:

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester having theformula:

In another embodiment, the present invention provides and relates to thefollowing compound or a salt thereof, as well as its preparation:

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid having the formula:

In another embodiment, the present invention provides and relates to thefollowing compound or a salt thereof, as well as its preparation:

{1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid havingthe formula:

In a further embodiment, the present invention provides and relates tothe following compound or a salt thereof, as well as its preparation:

wherein R is C₁-C₆ alkyl, preferably C₁-C₄ alkyl (such as e.g. methyl,ethyl, propyl, isopropyl, or the like), which may be preparedanalogously to the methyl ester as described herein and may be alsouseful as intermediates within the present invention.

In a further embodiment, the present invention provides and relates tothe following compound or a salt thereof, as well as its preparation:

wherein R is preferably C₁-C₆ alkyl, preferably C₁-C₄ alkyl (such ase.g. methyl, ethyl, propyl, isopropyl, or the like), which may beprepared analogously to the methyl ester as described herein and may bealso useful as intermediates within the present invention.

In a further embodiment, the present invention provides and relates tothe following compound or a salt thereof, as well as its preparation:

wherein R is C_(i)-C₆ alkyl, preferably C₁-C₄ alkyl (such as e.g.methyl, ethyl, propyl, isopropyl, or the like), which may be preparedanalogously to the methyl ester as described herein and may be alsouseful as intermediates within the present invention.

In certain embodiments, the present invention relates to an indicatedintermediate in isolated form, such as e.g. in solid or crystallineform.

In certain embodiments, the present invention relates to an indicatedintermediate in solution form.

Further, the present invention relates to spiro[2.5]octane-5,7-dioneobtainable or obtained by a process or method according to the presentinvention.

Further, the present invention relates in particular tospiro[2.5]octane-5,7-dione having the formula

obtainable or obtained by cyclization of[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester having theformula

such as e.g. substantially as described herein.

Further, the present invention relates in particular to a method ofpreparing spiro[2.5]octane-5,7-dione having the formula

said method comprising cyclizing [1-(2-oxo-propyl)-cyclopropyl]-aceticacid methyl ester having the formula

to form spiro[2.5]octane-5,7-dione, such as e.g. under conditionssubstantially as described herein by way of example in the followingexample, e.g. under Claisen condensation conditions in the presence of asuitable base (such as e.g. sodium methanolate) for enolisation, in asuitable solvent (such as e.g. tetrahydrofuran) at a suitable reactiontemperature.

Further on, the present invention relates to spiro[2.5]octane-5,7-dionehaving the formula

obtainable or obtained by cyclization of a[1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester such as having theformula

wherein R is C₁-C₆ alkyl, preferably C₁-C₄ alkyl (such as e.g. methyl,ethyl, propyl, isopropyl, or the like), more preferably C₁-C₃ alkyl oreven more preferably C₁-C₂ alkyl, particularly methyl, such as e.g.substantially as described herein or analogously thereto.

Further on, the present invention relates to a method of preparingspiro[2.5]octane-5,7-dione having the formula

said method comprising cyclizing [1-(2-oxo-propyl)-cyclopropyl]-aceticacid ester having the formula

wherein R is C₁-C₆ alkyl, preferably C₁-C₄ alkyl (such as e.g. methyl,ethyl, propyl, isopropyl, or the like), more preferably C₁-C₃ alkyl oreven more preferably C₁-C₂ alkyl, particularly methyl, to formspiro[2.5]octane-5,7-dione, such as e.g. under conditions substantiallyas described herein by way of example in the following example oranalogously or similarly thereto, e.g. under Claisen condensationconditions in the presence of a suitable base (such as e.g. therespective metal alcoholate, particularly sodium methanolate) forenolisation, in a suitable solvent (such as e.g. tetrahydrofuran) at asuitable reaction temperature.

The intermediates and final compound of the invention may be obtainedusing methods of synthesis known in principle. Preferably, theintermediates involved and the final compound may be obtained by thefollowing methods according to the invention which are described in moredetailed example hereinafter.

The process steps may be performed substantially as described herein byway of example. A process or method of this invention may comprise oneor more steps of converting and/or reacting the mentioned intermediateswith the appropriate reaction partners, suitably under conditions asdisclosed herein (e.g. by using the indicated reagents and/or solventsand/or temperatures, etc.).

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by gas chromatography (GC), High Pressure LiquidChromatography (HPLC) or Thin Layer Chromatography, if desired.

EXAMPLES

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

(1-Carboxymethyl-cyclopropyl)-acetic acid

300 g of (1-cyanomethyl-cyclopropyl)-acetonitrile (2.5 mole) arecombined with 3495 g of a 20% aqueous potassium hydroxide solution (12.5mole, 5 eq) and the mixture is slowly heated to reflux. After 7.5 hoursat reflux the mixture is cooled to room temperature and washed with 600ml methyl tert-butyl ether. The aqueous phase is acidified to pH 2.5,and extracted two times with a total volume of 1500 ml of2-methyltetrahydrofuran. The combined organic phases are washed withbrine (110 ml), filtered and evaporated to dryness to yield a colorlesssolid.

Yield: 354.4 g (90% of theory; 83% assay-corrected)

Purity (HPLC a/a): 92%

1H NMR (400 MHz, D2O): δH=2.29 (s, 4H), 0.43 (s, 4H) ppm.

6-Oxa-spiro[2.5]octane-5,7-dione

350 g crude (1-carboxymethyl-cyclopropyl)-acetic acid (2.2 mole, 92%purity, from step 1) are suspended in a mixture of 350 ml of mesityleneand 678 g of acetic anhydride (6.6 mole, 3 eq) and heated to 100° C.Upon reaching that temperature, the pressure is reduced to approximately200 mbar and 45% of the solvent mixture are distilled off (distillationtakes approx. 1 h). Then the mixture is slowly cooled to 0-5° C. and theprecipitate is collected by filtration. The filter cake is washed with87 ml of cold mesitylene and then dried in vaccuo at 40° C.

Yield: 252.1 g (81% of theory)

Purity (GC a/a): 99%

Mass spectrometry (EI+): m/z=140 [M]+

1H NMR (400 MHz, CDCl3): δH=2.61 (s, 4H), 0.63 (s, 4H) ppm.

Additional material can be obtained by concentrating the mother liquorto dryness and recrystallizing the residue from 3.5 vol of mesitylene(increasing the yield to 87%).

(1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid

To a suspension of 150 g 6-oxa-spiro[2.5]octane-5,7-dione (1.07 mole) in150 ml toluene are added 69 g methanol (2.1 mole, 2 eq) and 75 mg4-dimethylaminopyridine (0.06 mole-%). The mixture is heated underreflux (approx. 85° C.). After one hour the mixture is cooled to 40-50°C. and 150 ml of toluene are added. Then vacuum is applied and 180 g ofdistillate are removed from the reaction mixture. The remaining solutionis directly used in the next step. Purity (GC a/a, derivatization withN-methy-N-(trimethylsilyl)trifluoroacetamide): 98% 1H NMR (400 MHz,CDCl3): δH=11.44 (br s, 1H), 3.63 (s, 3H), 2.41 (s, 2H), 2.38 (s, 2H),0.52 (s, 4H) ppm.

By the use of the appropriate alcohols other than methanol (such as e.g.ethanol), the corresponding non-methyl esters (e.g. the ethyl ester) maybe obtained analogously or similarly to the procedure as described forthe methyl ester.

(1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester

The crude (1-methoxycarbonylmethyl-cyclopropyl)-acetic acid solutionfrom the previous step (containing approx. 184 g (1.07 mole)(1-methoxycarbonylmethyl-cyclopropyl)-acetic acid in 180 ml of toluene)is diluted with 120 ml of toluene. Ten drops of dimethylformamide areadded, the mixture is heated to 40° C. and a solution of 159 g ofthionyl chloride (1.34 mole, 1.25 eq) in 75 ml of toluene is addeddropwise. Then the mixture is slowly heated to 70° C. and stirred overnight. Then the solvent is removed by vacuum distillation and theresidue is co-evaporated three times with 185 ml of toluene each,yielding a dark oil.

Yield: 207.2 g (crude product, 102% (over two steps) of theory)

Purity (GC a/a, derivatization with isopropanol): 97%

1H NMR (400 MHz, CDCl3): δH=3.64 (s, 3H), 3.01 (s, 2H), 2.34 (s, 2H),0.56 (s, 4H) ppm.

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester

207.2 g crude (1-chlorocarbonylmethyl-cyclopropyl)-acetic acid methylester (approx. 1.07 mole, 97% purity, from step 4) are dissolved in 1428ml of a 3:1 mixture of tetrahydrofuran and toluene. The mixture iscooled to −50° C. and 6.3 g of iron(III)bromide (0.02 mole, 0.02 eq) areadded. Then 357 ml of methylmagnesium chloride in tetrahydrofuran (3 Msolution in tetrahydrofuran, 1.07 mole, 1.0 eq) are added dropwise overtwo hours. After in-process control another 55 ml of methylmagnesiumchloride in tetrahydrofuran (3 M solution in tetrahydrofuran, 0.17 mole,0.15 eq) are added dropwise. Stirring is continued for 40 min, then themixture is warmed to approx. 0° C., and diluted with 750 ml of methyltert-butyl ether. Then the mixture is transferred onto a mixture of 27ml of 37% hydrochloric acid and 480 ml of water. The phases areseparated and the aqueous phase is extracted with 480 ml of methyltert-butyl ether. The combined organic phases are washed twice with 480ml of water (each) and then with 210 ml of brine, then dried overmagnesium sulfate and evaporated to dryness to yield a dark red/brownoil.

Yield: 167.7 g (88% assay, 81% (over three steps) of theory)

Purity (GC): 92%

Mass spectrometry (EI+): m/z=170 [M]+, 155 [M-CH3]+

1H NMR (400 MHz, CDCl3): δH=3.66 (s, 3H), 2.53 (s, 2H), 2.36 (s, 2H),2.13 (s, 3H), 0.57-0.54 (m, 2H), 0.48-0.45 (m, 2H) ppm.

Spiro[2.5]octane-5,7-dione

23.3 g of crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester(60% purity, from step 5) are dissolved in 135 ml of tetrahydrofuran and17.1 g of a sodium methanolate solution in methanol (30% in methanol)are added at room temperature and the mixture is stirred for six hours.Then the solution is diluted with 135 ml of methyl tert-butyl ether andquenched with 135 ml of water. Stirring is continued for five minutes,then the phases are separated. The aqueous phase is extracted with 67.5ml of methyl tert-butyl ether, then acidified to pH 2-3 with 37% HCl andwashed twice with 67.5 ml of methyl tert-butyl ether each. The combinedorganic phases are washed with 18 ml of water and concentrated todryness. The crude product is stirred with 18 ml of cold methyltert-butyl ether and then the precipitate is isolated by filtration. Thefilter cake is washed with 18 ml of cold methyl tert-butyl ether toyield the product as an off-white solid.

Yield: 6.6 g (60% of theory)

Purity (HPLC a/a): 99.8%

Mass spectrometry (EI+): m/z=138 [M]+

1H NMR (400 MHz, CDCl3): δH=3.45 (s, 2H), 2.43 (s, 4H), 0.54 (s, 4H)(keto form); 10.14 (br s, 1H), 5.54 (s, 1H), 2.25 (s, 4H), 0.47 (s, 4H)(enol form) ppm.

Alternative:

Alternative Route I:

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid

To a solution of 4.4 g 6-oxa-spiro[2.5]octane-5,7-dione (31 mmole) in 66ml tetrahydrofuran are added 600 mg copper(I)chloride (6 mmole, 0.2 eq).The mixture is cooled to −20° C. and 9.8 ml of methylmagnesium bromidein 2-methyl tetrahydrofuran (3.2 M solution in 2-methyl tetrahydrofuran,31 mmole, 1.0 eq) are added dropwise over 0.5 hours. The mixture iswarmed to room temperature and stirred for 2 hours. 66 ml of water areadded and the mixture is acidified to pH 3.0 by addition of 20.4 g of 2M hydrochloric acid. 50 ml of methyl tert-butyl ether are added and thephases are separated. The aqueous phase is extracted again with 50 ml ofmethyl tert-butyl ether and the combined organic phases are washed with20 ml of brine and concentrated to dryness. The resulting crude productis directly used in the next step (esterification to[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester).

Yield: 4.9 g (crude)

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester

To a solution of 4.9 g crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid(31 mmole) in 73.5 ml methanol are added 1 ml of mesitylene (GCstandard) and 2.5 ml of conc. hydrochloric acid. The mixture is heatedto reflux for 1 hour and then concentrated to dryness. 40 ml of waterare added to the residue and the resulting mixture is extracted with 100ml of methyl tert-butyl ether in two portions. The combined organicphases are concentrated to dryness. The resulting crude product isdirectly used in the next step (spiro[2.5]octane-5,7-dione).

Yield: 5.3 g (crude)

Purity (GC a/a): 20.0%

By the use of the appropriate alcohols other than methanol (such as e.g.ethanol), the corresponding non-methyl esters (e.g. the ethyl ester) maybe obtained analogously or similarly to the procedure as described forthe methyl ester.

Spiro[2.5]octane-5,7-dione

Experimental details: See above

Yield: 0.33 g (8% over three steps)

Purity (GC a/a): 99.7%

Alternative Route II:

{1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid

To a mixture of 5 g 6-oxa-spiro[2.5]octane-5,7-dione (36 mmole), 3.8 gof N,O-dimethylhydroxylamine hydrochloride (39 mmole, 1.1 eq) and 75 mlof dichloromethane are added 7 ml of pyridine (78 mmole, 2.2 eq) at 0-5°C. The solution is warmed to room temperature, stirred over night andwashed with 50 ml of brine. The aqueous phase is extracted with 3×30 mlof dichloromethane and the combined organic phases are dried overmagnesium sulfate and evaporated to dryness. The resulting crude productis directly used in the next step ([1-(2-oxo-propyl)-cyclopropyl]-aceticacid).

Yield: 7.9 g (crude, 110% of theory)

Purity (HPLC a/a): >99.9%

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid

To a solution of 3.6 g crude{1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid (18mmole) in 54 ml of THF are added 24.5 ml of methyllithium (1.6 Msolution in diethyl ether, 39.2 mmole, 2.2 eq) at <−75° C. Stirring iscontinued for 2 hours, then the mixture is quenched by addition of 2 mlof methanol and warmed to room temperature. 54 ml of water are added andthe phases are separated. The aqueous product phase is washed with 27 mlof methyl tert-butyl ether, acidified to pH 2.5 by addition of conc. HCland extracted three times with 27 ml ethyl acetate each. The combinedorganic phases are concentrated to dryness and the residue is directlyused in the next step (esterification to[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester).

[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester

Experimental details: See above

Yield: 2.4 g (84% assay, 66% over three steps (assay-corrected))

Purity (GC a/a): 86.3%

1. A method of preparing spiro[2.5]octane-5,7-dione having the formula

said method comprising cyclizing a [1-(2-oxo-propyl)-cyclopropyl]-aceticacid ester, having the formula

wherein R is preferably C₁-C₆ alkyl, preferably C₁-C₄ alkyl, morepreferably C₁-C₃ alkyl or even more preferably C₁-C₂ alkyl, particularlymethyl, to form spiro[2.5]octane-5,7-dione.
 2. A process for themanufacture of spiro[2.5]octane-5,7-dione having the formula

said process comprising the following reaction steps (wherein R ispreferably C₁-C₆ alkyl, preferably C₁-C₄ alkyl, more preferably C₁-C₃alkyl or even more preferably C₁-C₂ alkyl, particularly methyl):


3. A process for the manufacture of spiro[2.5]octane-5,7-dione havingthe formula

said process comprising the following reaction steps, via route I or viaroute II, wherein R is preferably C₁-C₆ alkyl, preferably C₁-C₄ alkyl,more preferably C₁-C₃ alkyl or even more preferably C₁-C₂ alkyl,particularly methyl:


4. A compound useful as intermediate selected from a group consistingof: (1-Carboxymethyl-cyclopropyl)-acetic acid,6-Oxa-spiro[2.5]octane-5,7-dione,(1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid,(1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester,[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester,[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid, and{1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid, or atautomer or salt thereof.
 5. 6-Oxa-spiro[2.5]octane-5,7-dione having theformula:


6. (1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid having the formula:


7. (1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester havingthe formula:


8. [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester having theformula:


9. [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid having the formula:


10. {1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acidhaving the formula:


11. A compound of the following general formula

wherein R is C₁-C₆ alkyl, preferably C₁-C₄ alkyl.
 12. A compoundaccording to claim 4 in a salt form.
 13. A compound according to claim4, either in isolated form or in solution.
 14. One or more of thereaction steps of claim 2, or any combination of two or more successivesteps.
 15. One or more of the reaction steps of claim 3, or anycombination of two or more successive steps.
 16. The method according toclaim 1 wherein the [1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester,particularly [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester, issubjected to condensation conditions using a suitable base such as e.g.the respective sodium alcoholate, particularly sodium methanolate in asuitable solvent such as e.g. comprising tetrahydrofuran at a suitablereaction temperature for cyclization to form spiro[2.5]octane-5,7-dione.17. Use of a [1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester to preparespiro[2.5]octane-5,7-dione.